Diabetic nephropathy is the leading cause of ESRD, but its pathogenesis is controversial. The reason only some patients with IDDM or NIDDM develop overt nephropathy remains unknown. A large number of potential pathogenetic mechanisms postulated to cause or enhance renal damage, and shared with human diabetes, have been identified in rodent models. Nevertheless, IDDM models, including the widely used streptozotocin (STZ) induced diabetes model, are very resistant to the development of overt nephropathy. By contrast, some recently described NIDDM models do develop clinical and histologic nephropathy. The mechanisms critical to this differential susceptibility have not been defined. Using chronic BP radiotelemetry over 10 months, we have shown that partially-insulin treated STZ diabetes is associated with a significantly lower BP and postulated that such BP reductions may counteract the adverse effects of the other described pathogenetic mechanisms. We propose to test the hypothesis that the diabetic milieu although necessary, is not sufficient for the expression of the overt diabetic nephropathy and that an increased renal BP exposure is a necessary permissive factor. Specific Aim 1 will test the hypothesis that enhanced renal BP exposure acts synergystically with the diabetic milieu in the pathogenesis of overt diabetic nephropathy. Chronic BP radiotelemetry and BP power spectral analysis will be used to quantitate the total BP load and its individual components in nephropathy susceptible models (OLETF, SHROB, SHR/N-cp, ZSF) and their control strains. Dynamic BP transmission to the renal microvasculature will be quantitatively assessed by (i) renal autoregulatory capacity in conscious rats using renal arterial flow probes, with methods for data acquisition and analysis that have recently been developed in our laboratory and (ii) by direct micropuncture measurements of glomerular pressure (PGC) in anesthetized rats. If the hypothesis is valid, the variable rate and severity of the development of overt nephropathy in these models will correlate with the parameters of renal BP exposure. Specific Aim 2 will test the hypothesis that an enhanced renal BP exposure is necessary for the phenotypic expression of nephropathy in these models through pharmacologic reductions (antihypertensives) of specific components of the "BP-load". These data will be compared to that separately being obtained in the STZ diabetes model in normotensive and hypertensive rat strains so as to define the differences between IDDM and NIDDM models. These novel investigations should provide valuable new insights into the role of BP mechanisms in the pathogenesis of the overt diabetic nephropathy phenotype.